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Transcription-dependent and -independent signaling of RSK2 in cancer metastasis

癌症转移中 RSK2 的转录依赖性和非依赖性信号传导

基本信息

批准号：
10586091
负责人：
Sumin Kang
金额：
$ 36.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586091
关键词：
AMP-activated protein kinase kinase Anoikis Attenuated Biological Biological Availability Biological Process CREB1 gene Cause of Death Cell Death Induction Cells Cessation of life Clinical Clinical Treatment Combined Modality Therapy Complex Cytoprotection Data Disseminated Malignant Neoplasm Enzymes Genetic Genetic Transcription Glutamate Dehydrogenase Glutamates Homeostasis Human IRS1 gene In Vitro Invaded Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Pathway Metabolism Neoplasm Metastasis Oxidation-Reduction Pathway interactions Patients Pattern Phosphorylation Play Process Production Proliferating Property Proteins RPS6KA gene Reporting Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role STK11 gene Series Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Effect Treatment Efficacy Tumor Promotion Variant anti-cancer attenuation cancer cell cancer type cell type in vivo inhibitor knock-down lung cancer cell metabolic abnormality assessment metastatic process migration neoplastic cell novel patient derived xenograft model pharmacologic programs small molecule inhibitor stathmin transcription factor tumor upstream kinase

项目摘要

Metastasis is a complex biological process, which involves multiple signaling pathways. Therefore, a single agent is often insufficient and combination therapy is vitally important in the successful treatment of metastatic cancer. We reported that p90 ribosomal S6 kinase 2 (RSK2) promotes metastasis by activating multiple downstream substrates. In addition, we recently identified that glutamate dehydrogenase 1 (GDH1), a critical enzyme in the glutaminolysis pathway, provides anti-anoikis signals by activating CamKK2 and its downstream AMPK to regulate energy production, protecting cells from anoikis, and promoting metastasis in lung cancer. The effect of GDH1 is evident in LKB1-deficient cancer, where AMPK activation predominantly depends on CamKK2. This suggests that RSK2 and GDH1 are promising anti-metastasis targets. Indeed, targeting RSK2 or GDH1 by fmk (identified by our collaborator Jack Taunton at UCSF) or R162 (identified by our group) attenuated metastasis. We recently found that genetic or pharmacological inhibition of these two distinct signaling axes results in synergistic attenuation of cell invasion, migration, and anoikis resistance in LKB1-deficient lung cancer. Biological and metabolic studies revealed that the combined therapy further attenuates CREB activation. Intriguingly, GDH1 knockdown resulted in decreased activity of CamK4, another upstream kinase of CREB, suggesting that combined targeting of RSK2 and GDH1 may further attenuate CREB activity by inhibiting RSK2 and GDH1-CamKK2-CamK4 signaling involved CREB phosphorylation. In addition, combined targeting of RSK2 and GDH1 synergistically induced anoikis in LKB1 wild-type (wt) expressing cells and RSK2 directly phosphorylated LKB1, leading to AMPK activation. These data suggest that RSK2 may signal through LKB1 and AMPK to contribute to anoikis resistance in LKB1 wt cells. Thus, we hypothesize that RSK2 and GDH1 coordinately regulates AMPK and CREB in transcription- dependent and -independent manners to provide pro-metastatic potential in cancer cells. Thus, targeting both cellular and metabolic signaling by combination of RSK2 and GDH1 inhibitors is a promising anti-metastasis therapeutic strategy. We will use lung cancer with LKB1 or LKB1 null as a research platform. Three specific aims are proposed: (1) To demonstrate whether RSK2 and GDH1 coordinately provides anti-anoikis protection to cancer cells by activating AMPK through LKB1 and CamKK2, respectively; (2) To determine whether RSK2 and GDH1 together mediates migratory and pro-invasive signals by activating CREB and CREB transcription targets; (3) To validate whether RSK2 and GDH1 signaling correlates with metastatic potential in patient tumors and evaluate the therapeutic efficacy of targeting RSK2 and GDH1 in combination in treatment of metastatic cancers.

肿瘤转移是一个复杂的生物学过程，涉及多条信号通路。因此，一个单一的代理人联合治疗往往是不够的，联合治疗对于转移性癌症的成功治疗至关重要。我们报道了p90核糖体S6激酶2(RSK2)通过激活多个下游而促进肿瘤转移底物。此外，我们最近发现谷氨酸脱氢酶1(GDH1)是细胞内的一个关键酶。谷氨酰胺分解途径，通过激活CAMKK2及其下游的AMPK来提供抗失巢凋亡信号调节能量产生，保护细胞免受失巢凋亡，并促进肺癌的转移。的影响 GDH1在LKB1缺陷的癌症中很明显，AMPK的激活主要依赖于CAMKK2。这提示RSK2和GDH1是很有前景的抗肿瘤转移靶点。事实上，fmk针对RSK2或GDH1 (由加州大学旧金山分校的合作者Jack Taunton鉴定)或R162(由我们小组鉴定)可减弱转移。我们最近发现，遗传或药物抑制这两个不同的信号轴导致 LKB1基因缺陷的肺癌中细胞侵袭、迁移和失巢凋亡抵抗的协同减弱。生物学和代谢研究表明，联合治疗进一步减弱了CREB的激活。有趣的是，GDH1基因敲除导致另一种CREB上游激酶CamK4的活性降低，提示RSK2和GDH1的联合靶向可能通过抑制RSK2进一步减弱CREB的活性 GDH1-CAMKK2-CamK4信号参与CREB的磷酸化。此外，RSK2的联合靶向 GDH1协同诱导LKB1野生型(Wt)细胞和RSK2直接表达失巢磷酸化LKB1，导致AMPK激活。这些数据表明，RSK2可能通过LKB1和 AMPK参与LKB1wt细胞对失巢凋亡的抵抗。因此，我们假设RSK2和GDH1在转录过程中协调调节AMPK和CREB- 依赖和独立的方式在癌细胞中提供促进转移的潜力。因此，针对这两个目标 RSK2和GDH1抑制剂联合使用的细胞和代谢信号是一种有前途的抗肿瘤转移药物治疗策略。我们将以LKB1或LKB1缺失的肺癌为研究平台。三个具体目标建议：(1)证明RSK2和GDH1是否协同提供抗失巢细胞保护分别通过LKB1和CAMKK2激活AMPK；(2)确定RSK2和CAMKK2是否 GDH1通过激活CREB和CREB转录靶标共同介导迁移和侵袭信号； (3)验证RSK2和GDH1信号是否与患者肿瘤转移潜能和评价靶向RSK2和GDH1联合治疗转移性肿瘤的疗效。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis.

DOI：
10.1038/onc.2016.79
发表时间：
2016-10-13
期刊：
Oncogene
影响因子：
8
作者：
Alesi GN;Jin L;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Kang S
通讯作者：
Kang S

Mitochondrial metabolism-mediated redox regulation in cancer progression.

DOI：
10.1016/j.redox.2021.101870
发表时间：
2021-06
期刊：
Redox biology
影响因子：
11.4
作者：
Boese AC;Kang S
通讯作者：
Kang S

The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.

PLAG1-GDH1轴通过LKB1缺陷型肺癌中的CAMKK2-AMPK信号传导促进厌食症和肿瘤转移。

DOI：
10.1016/j.molcel.2017.11.025
发表时间：
2018-01-04
期刊：
Molecular cell
影响因子：
16
作者：
Jin L;Chun J;Pan C;Kumar A;Zhang G;Ha Y;Li D;Alesi GN;Kang Y;Zhou L;Yu WM;Magliocca KR;Khuri FR;Qu CK;Metallo C;Owonikoko TK;Kang S
通讯作者：
Kang S

Glutaminolysis as a target for cancer therapy.

DOI：
10.1038/onc.2015.447
发表时间：
2016-07-14
期刊：
Oncogene
影响因子：
8
作者：
Jin L;Alesi GN;Kang S
通讯作者：
Kang S

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.

DOI：
10.1038/onc.2017.6
发表时间：
2017-07-06
期刊：
Oncogene
影响因子：
8
作者：
Jin L;Chun J;Pan C;Alesi GN;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Fan J;Kang S
通讯作者：
Kang S